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1.
Front Endocrinol (Lausanne) ; 15: 1386230, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38962676

RESUMO

Background: Despite the evidence that energy balance is regulated differently in females and that the endocannabinoid system is sexually dimorphic, previous studies on the endocannabinoid system and energy balance predominantly used male models. Here, we characterize the effects of cannabinoid receptor deletion on body weight gain and glucose metabolism in female C57BL mice. Methods: Female mice lacking the cannabinoid-1 receptor (CB1R-/-), cannabinoid-2 receptor (CB2R-/-), or both receptors (CB1R-/-/CB2R-/-) and wild-type (WT) mice were fed with a low (LFD; 10% of calories from fat) or high-fat diet (HFD; 45% of calories from fat) for six weeks. Results: Female WT mice fed with HFD gained significantly more weight than WT mice fed with LFD (p < 0.001). Similar pattern was observed for CB2/- mice fed with HFD compared to CB2R-/- mice fed with LFD (p < 0.001), but not for CB1R-/- fed with HFD vs. LFD (p = 0.22) or CB1R-/-/CB2R-/- fed with HFD vs. LFD (p = 0.96). Comparing the 4 groups on LFD, weight gain of CB1R-/- mice was greater than all other genotypes (p < 0.05). When fed with HFD, the deletion of CB1R alone in females did not attenuate weight gain compared to WT mice (p = 0.72). Female CB1R-/-/CB2R-/- mice gained less weight than WT mice when fed with HFD (p = 0.007) despite similar food intake and locomotor activity, potentially owing to enhanced thermogenesis in the white adipose tissue. No significant difference in weight gain was observed for female CB2R-/- and WT mice on LFD or HFD. Fasting glucose, however, was higher in CB2R-/- mice fed with LFD than all other groups (p < 0.05). Conclusion: The effects of cannabinoid receptor deletion on glucose metabolism in female mice were similar to previously published findings on male mice, yet the effects on body weight gain and thermogenesis were attenuated in CB1R-/- mice.


Assuntos
Dieta Hiperlipídica , Metabolismo Energético , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor CB1 de Canabinoide , Receptor CB2 de Canabinoide , Aumento de Peso , Animais , Feminino , Camundongos , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/deficiência , Dieta Hiperlipídica/efeitos adversos , Aumento de Peso/genética , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/deficiência , Peso Corporal
2.
Addict Biol ; 29(7)2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38963015

RESUMO

The addictive use of nicotine contained in tobacco is associated with stressor-like emotional and cognitive effects such as anxiety and working memory impairment, and the involvement of epigenetic mechanisms such as histone acetylation has recently been reported. Although the precise nature of behavioural plasticity remains unclear, both anxiogenic- and working memory impairment-like effects were observed in the present experimental model of mice treated with repeated subcutaneous nicotine and/or immobilization stress, and these effects were commonly attenuated by the histone deacetylase (HDAC) inhibitors that induce histone acetylation. Such HDAC inhibitor-induced resilience was mimicked by ligands for the endocannabinoid (ECB) system, a neurotransmitter system that is closely associated with nicotine-induced addiction-related behaviours: the anxiogenic-like effects were mitigated by the cannabinoid type 1 (CB1) agonist arachidonylcyclopropylamide (ACPA), whereas the working memory impairment-like effects were mitigated by the CB1 antagonist SR 141716A. Moreover, the effects of the HDAC inhibitors were also mimicked by ligands for the endovanilloid (transient receptor potential vanilloid 1 [TRPV1]) system, a system that shares common characteristics with the ECB system: the anxiogenic-like effects were mitigated by the TRPV1 antagonist capsazepine, whereas the working memory impairment-like effects were mitigated by the TRPV1 agonist olvanil. Notably, the HDAC inhibitor-induced anxiolytic-like effects were attenuated by SR 141716A, which were further counteracted by capsazepine, whereas the working memory improvement-like effects were attenuated by capsazepine, which were further counteracted by SR 141716A. These results suggest the contribution of interrelated control of the ECB/TRPV1 systems and epigenetic processes such as histone acetylation to novel therapeutic approaches.


Assuntos
Ansiedade , Endocanabinoides , Epigênese Genética , Memória de Curto Prazo , Nicotina , Estresse Psicológico , Canais de Cátion TRPV , Animais , Canais de Cátion TRPV/efeitos dos fármacos , Nicotina/farmacologia , Camundongos , Memória de Curto Prazo/efeitos dos fármacos , Endocanabinoides/metabolismo , Masculino , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Receptor CB1 de Canabinoide/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Capsaicina/farmacologia , Capsaicina/análogos & derivados , Modelos Animais de Doenças , Rimonabanto/farmacologia , Agonistas Nicotínicos/farmacologia , Piperidinas/farmacologia
3.
Harm Reduct J ; 21(1): 127, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38951904

RESUMO

BACKGROUND: Since late 2019, fortification of 'regular' cannabis plant material with synthetic cannabinoid receptor agonists (SCRAs) has become a notable phenomenon on the drug market. As many SCRAs pose a higher health risk than genuine cannabis, recognizing SCRA-adulterated cannabis is important from a harm reduction perspective. However, this is not always an easy task as adulterated cannabis may only be distinguished from genuine cannabis by dedicated, often expensive and time-consuming analytical techniques. In addition, the dynamic nature of the SCRA market renders identification of fortified samples a challenging task. Therefore, we established and applied an in vitro cannabinoid receptor 1 (CB1) activity-based procedure to screen plant material for the presence of SCRAs. METHODS: The assay principle relies on the functional complementation of a split-nanoluciferase following recruitment of ß-arrestin 2 to activated CB1. A straightforward sample preparation, encompassing methanolic extraction and dilution, was optimized for plant matrices, including cannabis, spiked with 5 µg/mg of the SCRA CP55,940. RESULTS: The bioassay successfully detected all samples of a set (n = 24) of analytically confirmed authentic Spice products, additionally providing relevant information on the 'strength' of a preparation and whether different samples may have originated from separate batches or possibly the same production batch. Finally, the methodology was applied to assess the occurrence of SCRA adulteration in a large set (n = 252) of herbal materials collected at an international dance festival. This did not reveal any positives, i.e. there were no samples that yielded a relevant CB1 activation. CONCLUSION: In summary, we established SCRA screening of herbal materials as a new application for the activity-based CB1 bioassay. The simplicity of the sample preparation, the rapid results and the universal character of the bioassay render it an effective and future-proof tool for evaluating herbal materials for the presence of SCRAs, which is relevant in the context of harm reduction.


Assuntos
Agonistas de Receptores de Canabinoides , Cannabis , Cannabis/química , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Humanos , Contaminação de Medicamentos , Bioensaio , Canabinoides/análise
4.
Cells ; 13(13)2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38994954

RESUMO

Previous research highlighted the involvement of the cannabinoid CB1 receptor in regulating the physiology of hepatocytes and hepatic stellate cells. The inhibition of the CB1 receptor via peripherally restricted CB1 receptor inverse agonist JD5037 has shown promise in inhibiting liver fibrosis in mice treated with CCl4. However, its efficacy in phospholipid transporter-deficiency-induced liver fibrosis remains uncertain. In this study, we investigated the effectiveness of JD5037 in Mdr2-/- mice. Mdr2 (Abcb4) is a mouse ortholog of the human MDR3 (ABCB4) gene encoding for the canalicular phospholipid transporter. Genetic disruption of the Mdr2 gene in mice causes a complete absence of phosphatidylcholine from bile, leading to liver injury and fibrosis. Mdr2-/- mice develop spontaneous fibrosis during growth. JD5037 was orally administered to the mice for four weeks starting at eight weeks of age. Liver fibrosis, bile acid levels, inflammation, and injury were assessed. Additionally, JD5037 was administered to three-week-old mice to evaluate its preventive effects on fibrosis development. Our findings corroborate previous observations regarding global CB1 receptor inverse agonists. Four weeks of JD5037 treatment in eight-week-old Mdr2-/- mice with established fibrosis led to reduced body weight gains. However, contrary to expectations, JD5037 significantly exacerbated liver injury, evidenced by elevated serum ALT and ALP levels and exacerbated liver histology. Notably, JD5037-treated Mdr2-/- mice exhibited significantly heightened serum bile acid levels. Furthermore, JD5037 treatment intensified liver fibrosis, increased fibrogenic gene expression, stimulated ductular reaction, and upregulated hepatic proinflammatory cytokines. Importantly, JD5037 failed to prevent liver fibrosis formation in three-week-old Mdr2-/- mice. In summary, our study reveals the exacerbating effect of JD5037 on liver fibrosis in genetically MDR2-deficient mice. These findings underscore the need for caution in the use of peripherally restricted CB1R inverse agonists for liver fibrosis treatment, particularly in cases of dysfunctional hepatic phospholipid transporter.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 4 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Cirrose Hepática , Receptor CB1 de Canabinoide , Animais , Camundongos , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/agonistas , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência , Cirrose Hepática/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo , Masculino , Camundongos Knockout , Ácidos e Sais Biliares/metabolismo , Agonismo Inverso de Drogas , Camundongos Endogâmicos C57BL
5.
Int J Mol Sci ; 25(12)2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38928357

RESUMO

Cannabidiol (CBD), a phytocannabinoid, appeared to satisfy several criteria for a safe approach to preventing drug-taking behavior, including opioids. However, most successful preclinical and clinical results come from studies in adult males. We examined whether systemic injections of CBD (10 mg/kg, i.p.) during extinction of oxycodone (OXY, 3 mg/kg, i.p.) induced conditioned place preference (CPP) could attenuate the reinstatement of CPP brought about by OXY (1.5 mg/kg, i.p.) priming in adolescent rats of both sexes, and whether this effect is sex dependent. Accordingly, a priming dose of OXY produced reinstatement of the previously extinguished CPP in males and females. In both sexes, this effect was linked to locomotor sensitization that was blunted by CBD pretreatments. However, CBD was able to prevent the reinstatement of OXY-induced CPP only in adolescent males and this outcome was associated with an increased cannabinoid 1 receptor (CB1R) and a decreased mu opioid receptor (MOR) expression in the prefrontal cortex (PFC). The reinstatement of CCP in females was associated with a decreased MOR expression, but no changes were detected in CB1R in the hippocampus (HIP). Moreover, CBD administration during extinction significantly potentialized the reduced MOR expression in the PFC of males and showed a tendency to potentiate the reduced MOR in the HIP of females. Additionally, CBD reversed OXY-induced deficits of recognition memory only in males. These results suggest that CBD could reduce reinstatement to OXY seeking after a period of abstinence in adolescent male but not female rats. However, more investigation is required.


Assuntos
Canabidiol , Oxicodona , Receptor CB1 de Canabinoide , Receptores Opioides mu , Animais , Canabidiol/farmacologia , Masculino , Feminino , Oxicodona/farmacologia , Ratos , Receptor CB1 de Canabinoide/metabolismo , Receptores Opioides mu/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Analgésicos Opioides/farmacologia , Condicionamento Psicológico/efeitos dos fármacos
6.
Int J Mol Sci ; 25(12)2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38928415

RESUMO

Stroke is one of the leading causes of death. It not only affects adult people but also many children. It is estimated that, every year, 15 million people suffer a stroke worldwide. Among them, 5 million people die, while 5 million people are left permanently disabled. In this sense, the research to find new treatments should be accompanied with new therapies to combat neuronal death and to avoid developing cognitive impairment and dementia. Phytocannabinoids are among the compounds that have been used by mankind for the longest period of history. Their beneficial effects such as pain regulation or neuroprotection are widely known and make them possible therapeutic agents with high potential. These compounds bind cannabinoid receptors CB1 and CB2. Unfortunately, the psychoactive side effect has displaced them in the vast majority of areas. Thus, progress in the research and development of new compounds that show efficiency as neuroprotectors without this psychoactive effect is essential. On the one hand, these compounds could selectively bind the CB2 receptor that does not show psychoactive effects and, in glia, has opened new avenues in this field of research, shedding new light on the use of cannabinoid receptors as therapeutic targets to combat neurodegenerative diseases such as Alzheimer's, Parkinson's disease, or stroke. On the other hand, a new possibility lies in the formation of heteromers containing cannabinoid receptors. Heteromers are new functional units that show new properties compared to the individual protomers. Thus, they represent a new possibility that may offer the beneficial effects of cannabinoids devoid of the unwanted psychoactive effect. Nowadays, the approval of a mixture of CBD (cannabidiol) and Δ9-THC (tetrahydrocannabinol) to treat the neuropathic pain and spasticity in multiple sclerosis or purified cannabidiol to combat pediatric epilepsy have opened new therapeutic possibilities in the field of cannabinoids and returned these compounds to the front line of research to treat pathologies as relevant as stroke.


Assuntos
Canabidiol , AVC Isquêmico , Receptor CB1 de Canabinoide , Receptor CB2 de Canabinoide , Humanos , Receptor CB2 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/metabolismo , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/metabolismo , Animais , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/farmacologia
7.
Cells ; 13(11)2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38891114

RESUMO

Presynaptic Ca2+ influx through voltage-gated Ca2+ channels (VGCCs) is a key signal for synaptic vesicle release. Synaptic neurexins can partially determine the strength of transmission by regulating VGCCs. However, it is unknown whether neurexins modulate Ca2+ influx via all VGCC subtypes similarly. Here, we performed live cell imaging of synaptic boutons from primary hippocampal neurons with a Ca2+ indicator. We used the expression of inactive and active Cre recombinase to compare control to conditional knockout neurons lacking either all or selected neurexin variants. We found that reduced total presynaptic Ca2+ transients caused by the deletion of all neurexins were primarily due to the reduced contribution of P/Q-type VGCCs. The deletion of neurexin1α alone also reduced the total presynaptic Ca2+ influx but increased Ca2+ influx via N-type VGCCs. Moreover, we tested whether the decrease in Ca2+ influx induced by activation of cannabinoid receptor 1 (CB1-receptor) is modulated by neurexins. Unlike earlier observations emphasizing a role for ß-neurexins, we found that the decrease in presynaptic Ca2+ transients induced by CB1-receptor activation depended more strongly on the presence of α-neurexins in hippocampal neurons. Together, our results suggest that neurexins have unique roles in the modulation of presynaptic Ca2+ influx through VGCC subtypes and that different neurexin variants may affect specific VGCCs.


Assuntos
Cálcio , Hipocampo , Terminações Pré-Sinápticas , Animais , Cálcio/metabolismo , Terminações Pré-Sinápticas/metabolismo , Hipocampo/metabolismo , Hipocampo/citologia , Camundongos , Camundongos Knockout , Canais de Cálcio/metabolismo , Canais de Cálcio/genética , Neurônios/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/genética , Sinalização do Cálcio , Técnicas de Inativação de Genes , Neurexinas
8.
Proc Natl Acad Sci U S A ; 121(24): e2321532121, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38830102

RESUMO

Cannabis sativa is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, Δ9-tetrahydrocannabinol (THC), and other agonists engage the orthosteric site of CB1, activating both Gi and ß-arrestin signaling pathways. The activation of diverse pathways could result in on-target side effects and cannabis addiction, which may hinder therapeutic potential. A significant challenge in pharmacology is the design of a ligand that can modulate specific signaling of CB1. By leveraging insights from the structure-function selectivity relationship (SFSR), we have identified Gi signaling-biased agonist-allosteric modulators (ago-BAMs). Further, two cryoelectron microscopy (cryo-EM) structures reveal the binding mode of ago-BAM at the extrahelical allosteric site of CB1. Combining mutagenesis and pharmacological studies, we elucidated the detailed mechanism of ago-BAM-mediated biased signaling. Notably, ago-BAM CB-05 demonstrated analgesic efficacy with fewer side effects, minimal drug toxicity and no cannabis addiction in mouse pain models. In summary, our finding not only suggests that ago-BAMs of CB1 provide a potential nonopioid strategy for pain management but also sheds light on BAM identification for GPCRs.


Assuntos
Microscopia Crioeletrônica , Receptor CB1 de Canabinoide , Transdução de Sinais , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/química , Animais , Regulação Alostérica/efeitos dos fármacos , Camundongos , Humanos , Transdução de Sinais/efeitos dos fármacos , Proteínas de Ligação ao GTP/metabolismo , Proteínas de Ligação ao GTP/genética , Células HEK293 , Relação Estrutura-Atividade , Dronabinol/farmacologia , Dronabinol/química , Dronabinol/análogos & derivados , Cannabis/química , Cannabis/metabolismo
9.
Obesity (Silver Spring) ; 32(7): 1235-1244, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38887179

RESUMO

Targeting the cannabinoid type 1 receptor (CB1) is a clinically validated antiobesity therapeutic approach. The only such drug approved, rimonabant, was launched in 2006 in Europe but subsequently rejected by the US Food and Drug Administration (FDA) in 2007. The FDA cited the increased risk of suicidality in its opposition to rimonabant's approval, leading to the drug's eventual worldwide withdrawal and the abandonment of this class of therapeutics. Seventeen years later, a new class of CB1-targeting drugs is emerging, but the impact of the 2007 FDA decision remains a formidable obstacle to its clinical development. We revisit the suicidality data presented by the FDA in light of the evolution of suicidality assessment and cross-reference this with the data in the subsequently published clinical trials. We conclude that the publicly available data do not support the FDA's conclusion that the use of rimonabant was associated with an increase in the risk of suicidality.


Assuntos
Fármacos Antiobesidade , Rimonabanto , Suicídio , United States Food and Drug Administration , Humanos , Estados Unidos/epidemiologia , Fármacos Antiobesidade/efeitos adversos , Suicídio/estatística & dados numéricos , Suicídio/psicologia , Obesidade/psicologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Antagonistas de Receptores de Canabinoides , Aprovação de Drogas , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos
10.
PLoS One ; 19(6): e0305868, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38913661

RESUMO

The cannabinoid receptor type 1 (CB1R) is a promising therapeutic target for various neurodegenerative diseases, including HIV-1-associated neurocognitive disorder (HAND). However, the therapeutic potential of CB1R by direct activation is limited due to its psychoactive side effects. Therefore, research has focused on indirectly activating the CB1R by utilizing positive allosteric modulators (PAMs). Studies have shown that CB1R PAMs (ZCZ011 and GAT211) are effective in mouse models of Huntington's disease and neuropathic pain, and hence, we assess the therapeutic potential of ZCZ011 in a well-established mouse model of neuroHIV. The current study investigates the effect of chronic ZCZ011 treatment (14 days) on various behavioral paradigms and the endocannabinoid system in HIV-1 Tat transgenic female and male mice. Chronic ZCZ011 treatment (10 mg/kg) did not alter body mass, locomotor activity, or anxiety-like behavior regardless of sex or genotype. However, differential effects were noted in hot plate latency, motor coordination, and recognition memory in female mice only, with ZCZ011 treatment increasing hot plate latency and improving motor coordination and recognition memory. Only minor effects or no alterations were seen in the endocannabinoid system and related lipids except in the cerebellum, where the effect of ZCZ011 was more pronounced in female mice. Moreover, AEA and PEA levels in the cerebellum were positively correlated with improved motor coordination in female mice. In summary, these findings indicate that chronic ZCZ011 treatment has differential effects on antinociception, motor coordination, and memory, based on sex and HIV-1 Tat expression, making CB1R PAMs potential treatment options for HAND without the psychoactive side effects.


Assuntos
Endocanabinoides , Camundongos Transgênicos , Receptor CB1 de Canabinoide , Produtos do Gene tat do Vírus da Imunodeficiência Humana , Animais , Feminino , Masculino , Endocanabinoides/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/genética , Camundongos , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , HIV-1/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Modelos Animais de Doenças
11.
Appl Microbiol Biotechnol ; 108(1): 380, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38888634

RESUMO

Obstructive sleep apnea (OSA) can lead to intestinal injury, endotoxemia, and disturbance of intestinal flora. Additionally, as a crucial component of the endocannabinoid system, some studies have demonstrated that cannabinoid 1 (CB1) receptors are closely linked to the multiple organ dysfunction triggered by OSA. However, the role of the CB1 receptor in alleviating OSA-induced colon injury remains unclear. Here, through the construction of the OSA classic model, we found that the colon tissue of chronic intermittent hypoxia (CIH)-induced mice exhibited an overexpression of the CB1 receptor. The results of hematoxylin-eosin staining and transmission electron microscopy revealed that inhibition of the CB1 receptor could decrease the gap between the mucosa and muscularis mucosae, alleviate mitochondrial swelling, reduce microvilli shedding, and promote the recovery of tight junctions of CIH-induced mice. Furthermore, CB1 receptor inhibition reduced the levels of metabolic endotoxemia and inflammatory responses, exhibiting significant protective effects on the colon injury caused by CIH. At the molecular level, through western blotting and real-time polymerase chain reaction techniques, we found that inhibiting the CB1 receptor can significantly increase the expression of ZO-1 and Occludin proteins, which are closely related to the maintenance of intestinal mucosal barrier function. Through 16S rRNA high-throughput sequencing and short-chain fatty acid (SCFA) determination, we found that inhibition of the CB1 receptor increased the diversity of the microbial flora and controlled the makeup of intestinal flora. Moreover, butyric acid concentration and the amount of SCFA-producing bacteria, such as Ruminococcaceae and Lachnospiraceae, were both markedly elevated by CB1 receptor inhibition. The results of the spearman correlation study indicated that Lachnospiraceae showed a positive association with both ZO-1 and Occludin but was negatively correlated with the colon CB1 receptor, IL-1ß, and TNF-α. According to this study, we found that inhibiting CB1 receptor can improve CIH-induced colon injury by regulating gut microbiota, reducing mucosal damage and promoting tight junction recovery. KEY POINTS: •CIH leads to overexpression of CB1 receptor in colon tissue. •CIH causes intestinal flora disorder, intestinal mucosal damage, and disruption of tight junctions. •Inhibition of CB1 receptor can alleviate the colon injury caused by CIH through regulating the gut microbiota, reducing mucosal injury, and promoting tight junction recovery.


Assuntos
Colo , Modelos Animais de Doenças , Mucosa Intestinal , Receptor CB1 de Canabinoide , Animais , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/genética , Camundongos , Colo/patologia , Colo/microbiologia , Colo/metabolismo , Masculino , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Hipóxia/metabolismo , Camundongos Endogâmicos C57BL , Proteína da Zônula de Oclusão-1/metabolismo , Ocludina/metabolismo , Ocludina/genética , Microbioma Gastrointestinal , Junções Íntimas/metabolismo
12.
J Cell Sci ; 137(11)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38864427

RESUMO

Endocannabinoid signalling mediated by cannabinoid receptor 1 (CB1R, also known as CNR1) is critical for homeostatic neuromodulation of both excitatory and inhibitory synapses. This requires highly polarised axonal surface expression of CB1R, but how this is achieved remains unclear. We previously reported that the α-helical H9 domain in the intracellular C terminus of CB1R contributes to axonal surface expression by an unknown mechanism. Here, we show in rat primary neuronal cultures that the H9 domain binds to the endocytic adaptor protein SGIP1 to promote CB1R expression in the axonal membrane. Overexpression of SGIP1 increases CB1R axonal surface localisation but has no effect on CB1R lacking the H9 domain (CB1RΔH9). Conversely, SGIP1 knockdown reduces axonal surface expression of CB1R but does not affect CB1RΔH9. Furthermore, SGIP1 knockdown diminishes CB1R-mediated inhibition of presynaptic Ca2+ influx in response to neuronal activity. Taken together, these data advance mechanistic understanding of endocannabinoid signalling by demonstrating that SGIP1 interaction with the H9 domain underpins axonal CB1R surface expression to regulate presynaptic responsiveness.


Assuntos
Axônios , Ligação Proteica , Receptor CB1 de Canabinoide , Animais , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/genética , Axônios/metabolismo , Ratos , Domínios Proteicos , Humanos , Células Cultivadas , Neurônios/metabolismo , Ratos Sprague-Dawley , Membrana Celular/metabolismo
13.
Int J Mol Sci ; 25(11)2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38892247

RESUMO

Yeast expression of human G-protein-coupled receptors (GPCRs) can be used as a biosensor platform for the detection of pharmaceuticals. Cannabinoid receptor type 1 (CB1R) is of particular interest, given the cornucopia of natural and synthetic cannabinoids being explored as therapeutics. We show for the first time that engineering the N-terminus of CB1R allows for efficient signal transduction in yeast, and that engineering the sterol composition of the yeast membrane modulates its performance. Using an engineered cannabinoid biosensor, we demonstrate that large libraries of synthetic cannabinoids and terpenes can be quickly screened to elucidate known and novel structure-activity relationships. The biosensor strains offer a ready platform for evaluating the activity of new synthetic cannabinoids, monitoring drugs of abuse, and developing therapeutic molecules.


Assuntos
Técnicas Biossensoriais , Canabinoides , Receptor CB1 de Canabinoide , Saccharomyces cerevisiae , Técnicas Biossensoriais/métodos , Humanos , Canabinoides/química , Canabinoides/farmacologia , Canabinoides/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/genética , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Relação Estrutura-Atividade , Transdução de Sinais/efeitos dos fármacos
14.
Neurochem Res ; 49(8): 2165-2178, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38824460

RESUMO

Patients suffering from hepatic ischemia-reperfusion injury (HIRI) frequently exhibit postoperative cognitive deficits. Our previous observations have emphasized the diurnal variation in hepatic ischemia-reperfusion injury-induced cognitive impairment, in which gut microbiota-associated hippocampal lipid metabolism plays an important role. Herein, we further investigated the molecular mechanisms involved in the process. Hepatic ischemia-reperfusion surgery was performed under morning (ZT0, 08:00) and evening (ZT12, 20:00). Fecal microbiota transplantation was used to associate HIRI model with pseudo-germ-free mice. The novel object recognition test and Y-maze test were used to assess cognitive function. 16S rRNA gene sequencing and analysis were used for microbial analysis. Western blotting was used for hippocampal protein analysis. Compared with the ZT0-HIRI group, ZT12-HIRI mice showed learning and short term memory impairment, accompanied by down-regulated expression of hippocampal CB1R, but not CB2R. Both gut microbiota composition and microbiota metabolites were significantly different in ZT12-HIRI mice compared with ZT0-HIRI. Fecal microbiota transplantation from the ZT12-HIRI was demonstrated to induce cognitive impairment behavior and down-regulated hippocampal CB1R and ß-arrestin1. Intraperitoneal administration of CB1R inhibitor AM251 (1 mg/kg) down-regulated hippocampal CB1R and caused cognitive impairment in ZT0-HIRI mice. And intraperitoneal administration of CB1R agonist WIN 55,212-2 (1 mg/kg) up-regulated hippocampal CB1R and improved cognitive impairment in ZT12-HIRI mice. In summary, the results suggest that gut microbiota may regulate the diurnal variation of HIRI-induced cognitive function by interfering with hippocampal CB1R.


Assuntos
Disfunção Cognitiva , Microbioma Gastrointestinal , Hipocampo , Receptor CB1 de Canabinoide , Traumatismo por Reperfusão , Animais , Microbioma Gastrointestinal/fisiologia , Hipocampo/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/etiologia , Traumatismo por Reperfusão/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ritmo Circadiano/fisiologia , Fígado/metabolismo , Transplante de Microbiota Fecal , Aprendizagem em Labirinto/fisiologia
15.
Mult Scler Relat Disord ; 87: 105659, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38704874

RESUMO

BACKGROUND/AIM: The roles of endocannabinoids are described in immune modulation and neuroprotection. HTLV-1-associated myelopathy (HAM/TSP) is an inflammatory neurodegenerative disease. Therefore, in this study, the interactions of HTLV-1 regulatory factors and host cannabinoid receptors (CBRs) were evaluated in HAM/TSP. METHODS: Nineteen HAM/TSPs, 22 asymptomatic carriers (ACs), and 18 healthy controls (HCs) were enrolled. RNA was extracted from PBMCs and then reverse-transcribed to cDNA. The gene expression of CB1R and CB2R, as well as HTLV-1 proviral load (PVL), Tax and HTLV-1 basic leucine zipper factor (HBZ) were assessed by RT-qPCR. RESULTS: The mean expression of CB1R in ACs (8.51 ± 2.76) was significantly higher than HAMTSPs (1.593 ± 0.74, p = 0.05) and also HCs (0.10 ± 0.039, p = 0.001). The CB2R gene expression level in ACs (2.62±0.44) was significantly higher than HAM/TSPs (0.59 ± 0.15, p = 0.001) and HCs (1.00 ± 0.2, p = 0.006). Meanwhile there was a strong correlation between CB1R and CB2R gene expression levels in the HCs and HAM/TSPs (p = 0.001). HTLV-1-Tax expression in HAM/TSPs (386 ± 104) was higher than ACs (75 ± 32) and statistically significant (p = 0.003). While HTLV-1-HBZ was only expressed in three AC subjects and five HAM/TSPs, thus it cannot be analyzed. CONCLUSION: The up-regulation of CB2R has immunomodulatory effects in inflammatory reactions. While CB1R as a neuroprotective agent may suppress inflammatory reactions in ACs, preventing HAM/TSP. It seems that, like multiple sclerosis (MS), cannabinoid medications are beneficial in HAM/TSP.


Assuntos
Vírus Linfotrópico T Tipo 1 Humano , Paraparesia Espástica Tropical , Receptor CB1 de Canabinoide , Receptor CB2 de Canabinoide , Humanos , Masculino , Feminino , Receptor CB1 de Canabinoide/metabolismo , Adulto , Receptor CB2 de Canabinoide/metabolismo , Pessoa de Meia-Idade , Produtos do Gene tax/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Carga Viral , Proteínas dos Retroviridae/metabolismo
16.
Neuropharmacology ; 256: 110018, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-38810925

RESUMO

Diets high in sucrose and fat are becoming more prevalent the world over, accompanied by a raised prevalence of cardiovascular diseases, cancers, diabetes, obesity, and metabolic syndrome. Clinical studies link unhealthy diets with the development of mental health disorders, particularly depression. Here, we investigate the effects of 12 days of sucrose consumption administered as 2 L of 25% sucrose solution daily for 12 days in Göttingen minipigs on the function of brain receptors involved in reward and motivation, regulating feeding, and pre- and post-synaptic mechanisms. Through quantitative autoradiography of cryostat sections containing limbic brain regions, we investigated the effects of sucrose restricted to a 1-h period each morning, on the specific binding of [3H]raclopride on dopamine D2/3 receptors, [3H]UCB-J at synaptic vesicle glycoprotein 2A (SV2A), [3H]MPEPγ at metabotropic glutamate receptor subtype 5 (mGluR5) and [3H]SR141716A at the cannabinoid receptor 1 (CB1). Compared to control diet animals, the sucrose group showed significantly lower [3H]UCB-J and [3H]MPEPγ binding in the prefrontal cortex. The sucrose-consuming minipigs showed higher hippocampal CB1 binding, but unaltered dopamine D2/3 binding compared to the control group. We found that the sucrose diet reduced the synaptic density marker while increasing CB1 binding in limbic brain structures, which may subserve maladaptive changes in appetite regulation and feeding. Further studies of the effects of diets and lifestyle habits on brain neuroreceptor and synaptic density markers are warranted.


Assuntos
Sacarose , Porco Miniatura , Animais , Suínos , Sacarose/administração & dosagem , Masculino , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptores de Canabinoides/metabolismo , Sinapses/metabolismo , Sinapses/efeitos dos fármacos , Receptor CB1 de Canabinoide/metabolismo , Receptores de Dopamina D2/metabolismo , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Feminino , Receptores de Dopamina D3/metabolismo
17.
Int J Mol Sci ; 25(9)2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38732230

RESUMO

Cannabinoid receptors CB1R and CB2R are G-protein coupled receptors acted upon by endocannabinoids (eCBs), namely 2-arachidonoylglycerol (2-AG) and N-arachidonoyl ethanolamine (AEA), with unique pharmacology and modulate disparate physiological processes. A genetically encoded GPCR activation-based sensor that was developed recently-GRABeCB2.0-has been shown to be capable of monitoring real-time changes in eCB levels in cultured cells and preclinical models. However, its responsiveness to exogenous synthetic cannabinoid agents, particularly antagonists and allosteric modulators, has not been extensively characterized. This current study expands upon the pharmacological characteristics of GRABeCB2.0 to enhance the understanding of fluorescent signal alterations in response to various functionally indiscriminate cannabinoid ligands. The results from this study could enhance the utility of the GRABeCB2.0 sensor for in vitro as well as in vivo studies of cannabinoid action and may aid in the development of novel ligands.


Assuntos
Endocanabinoides , Receptor CB1 de Canabinoide , Receptor CB2 de Canabinoide , Humanos , Receptor CB2 de Canabinoide/metabolismo , Endocanabinoides/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Células HEK293 , Ligantes , Glicerídeos/farmacologia , Técnicas Biossensoriais/métodos , Moduladores de Receptores de Canabinoides/farmacologia , Animais , Ácidos Araquidônicos/farmacologia , Ácidos Araquidônicos/metabolismo
18.
Int J Mol Sci ; 25(10)2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38791212

RESUMO

Alcohol use disorder (AUD) is a significant issue affecting women, with severe consequences for society, the economy, and most importantly, health. Both personality and alcohol use disorders are phenotypically very complex, and elucidating their shared heritability is a challenge for medical genetics. Therefore, our study investigated the correlations between the microsatellite polymorphism (AAT)n of the Cannabinoid Receptor 1 (CNR1) gene and personality traits in women with AUD. The study group included 187 female subjects. Of these, 93 were diagnosed with alcohol use disorder, and 94 were controls. Repeat length polymorphism of microsatellite regions (AAT)n in the CNR1 gene was identified with PCR. All participants were assessed with the Mini-International Neuropsychiatric Interview and completed the NEO Five-Factor and State-Trait Anxiety Inventories. In the group of AUD subjects, significantly fewer (AAT)n repeats were present when compared with controls (p = 0.0380). While comparing the alcohol use disorder subjects (AUD) and the controls, we observed significantly higher scores on the STAI trait (p < 0.00001) and state scales (p = 0.0001) and on the NEO Five-Factor Inventory Neuroticism (p < 0.00001) and Openness (p = 0.0237; insignificant after Bonferroni correction) scales. Significantly lower results were obtained on the NEO-FFI Extraversion (p = 0.00003), Agreeability (p < 0.00001) and Conscientiousness (p < 0.00001) scales by the AUD subjects when compared to controls. There was no statistically significant Pearson's linear correlation between the number of (AAT)n repeats in the CNR1 gene and the STAI and NEO Five-Factor Inventory scores in the group of AUD subjects. In contrast, Pearson's linear correlation analysis in controls showed a positive correlation between the number of the (AAT)n repeats and the STAI state scale (r = 0.184; p = 0.011; insignificant after Bonferroni correction) and a negative correlation with the NEO-FFI Openness scale (r = -0.241; p = 0.001). Interestingly, our study provided data on two separate complex issues, i.e., (1) the association of (AAT)n CNR1 repeats with the AUD in females; (2) the correlation of (AAT)n CNR1 repeats with anxiety as a state and Openness in non-alcohol dependent subjects. In conclusion, our study provided a plethora of valuable data for improving our understanding of alcohol use disorder and anxiety.


Assuntos
Alcoolismo , Personalidade , Receptor CB1 de Canabinoide , Humanos , Feminino , Receptor CB1 de Canabinoide/genética , Adulto , Alcoolismo/genética , Alcoolismo/psicologia , Personalidade/genética , Pessoa de Meia-Idade , Repetições de Microssatélites/genética , Polimorfismo Genético , Estudos de Casos e Controles , Predisposição Genética para Doença
19.
J Pregnancy ; 2024: 6620156, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38745869

RESUMO

Background: The cannabinoid receptor (CBR) plays a significant role in oogenesis, pregnancy, and childbirth. It might also play a significant role in preterm birth (PTB). The aim of the study was to investigate the association between the expression of the CBR in the placenta and the incidence of PTB. Methods: This prospective, observational, multicentre preliminary study was conducted on placental samples obtained from 109 women. The study included 95 patients hospitalized due to the high risk of PTB. They were divided into two groups: Group 1, where the expression of the CBR1 and CBR1a was analyzed, and Group 2, in which we examined CBR2 expression. The control group, that is, Group 3, consisted of 14 women who delivered at term, and their placentas were tested for the presence of all three receptor types (CBR1, CBR1a, and CBR2). Results: The study used reverse transcription and real-time PCR methods to assess the expression of CBRs in the placental tissues. The expression of the CBR2, CBR1, and CBR1a receptors was significantly lower in the placentas of women after PTB compared to those after term births, p = 0.038, 0.033, and 0.034, respectively. Conclusions: The presence of CBR mRNA in the human placental tissue was confirmed. The decreased expression of CBRs could serve as an indicator in predicting PTB.


Assuntos
Placenta , Nascimento Prematuro , Receptor CB1 de Canabinoide , Receptor CB2 de Canabinoide , Humanos , Feminino , Gravidez , Placenta/metabolismo , Nascimento Prematuro/metabolismo , Estudos Prospectivos , Adulto , Receptor CB2 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/genética , Estudos de Casos e Controles , RNA Mensageiro/metabolismo , Receptores de Canabinoides/metabolismo , Receptores de Canabinoides/genética
20.
Rev Assoc Med Bras (1992) ; 70(5): e20231333, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38775505

RESUMO

OBJECTIVE: In this study, the effects of leptin, cannabinoid-1 (CB1) receptor agonist ACEA and antagonist AM251, and the interactions between leptin and CB1 receptor agonist/antagonist on oxidant and antioxidant enzymes in the cerebrum, cerebellum, and pedunculus cerebri tissue samples were investigated in the penicillin-induced epileptic model. METHODS: Male Wistar albino rats (n=56) were included in this study. In anesthetized animals, 500 IU penicillin-G potassium was injected into the cortex to induce epileptiform activity. Leptin (1 µg), ACEA (7.5 µg), AM251 (0.25 µg), and the combinations of the leptin+ACEA and leptin+AM251 were administered intracerebroventricularly (i.c.v.) after penicillin injections. Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) levels were measured in the cerebral tissue samples and plasma with the ELISA method. RESULTS: MDA levels increased, while SOD and GPx levels decreased after penicillin injection in the cerebrum and cerebellum. The efficacy of penicillin on SOD, MDA and GPx levels was further enhanced after leptin or AM251 injections. Whereas, ACEA decreased the MDA levels and increased GPx levels compared with the penicillin group. Administration of AM251+leptin did not change any oxidation parameter compared with the AM251. Furthermore, co-administration of ACEA and leptin significantly increased oxidative stress compared with the ACEA-treated group by increasing MDA and decreasing GPx levels. CONCLUSION: It was concluded that leptin reversed the effect of ACEA on oxidative stress. Co-administration of AM251 and leptin did not change oxidative stress compared with the AM251-treated group suggesting AM251 and leptin affect oxidative stress using the same pathways.


Assuntos
Epilepsia , Leptina , Malondialdeído , Piperidinas , Pirazóis , Ratos Wistar , Receptor CB1 de Canabinoide , Superóxido Dismutase , Animais , Leptina/farmacologia , Masculino , Receptor CB1 de Canabinoide/agonistas , Epilepsia/tratamento farmacológico , Epilepsia/induzido quimicamente , Malondialdeído/análise , Superóxido Dismutase/metabolismo , Superóxido Dismutase/análise , Piperidinas/farmacologia , Pirazóis/farmacologia , Glutationa Peroxidase/metabolismo , Glutationa Peroxidase/análise , Ácidos Araquidônicos/farmacologia , Ratos , Estresse Oxidativo/efeitos dos fármacos , Modelos Animais de Doenças , Penicilinas , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cérebro/efeitos dos fármacos , Cérebro/metabolismo , Ensaio de Imunoadsorção Enzimática , Agonistas de Receptores de Canabinoides/farmacologia
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